Summary: The class of mammalian biologically active polypeptides called growth factors influence the proliferation, differentiation, motility, maintenance and apoptosis of target cells. On-going studies in my laboratory are directed towards understanding the mechanism of action and biological role of growth factors which signal through the ErbB family of receptors . To address these issues, we utilize techniques common to protein biochemistry, cell biology and molecular biology. The ErbB family of receptors which include the epidermal growth factor receptor (EGFR), ErbB2, ErbB3 and ErbB4 mediate the biological actions of a family of growth factors which are structurally related to EGF. Members of this family of mitogens such as EGF and amphiregulin require the presence of the EGFR on cells for signaling, whereas signal transduction by the heregulins (HRGs; neu differentiation factor, neuregulin, acetylcholine receptor-inducing activity, glial growth factor) is initiated via an interaction with either ErbB3 or ErbB4. Previous work from our laboratory has demonstrated that the Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase SHP-2 is an essential positive mediator of ligand-induced signalling by all of the ErbB receptors (Deb et al., 1998). We found that there was a common requirement for the catalytic activity and both SH2 domains in mitogen-activated protein (MAP) kinase activation by EGF and the heregulins. However, at the present time the mechanism of action and substrate target responsible for this SHP-2 function is unknown. To better understand this function we are generating mutant forms of SHP-2 which are constitutively-activated in vitro and evaluating the ability of these mutants to signal in cells in the absence of ErbB activation or extracellular stimuli. A mechanistic evaluation of these data will provide information regarding downstream targets of SHP-2 and position SHP-2 function within the well characterized MAP kinase cascade.